In 1976, an explosion at the ICMESA plant in Seveso, Italy exposed the surrounding population to perhaps the highest levels of 2,3,7,8-tetrachlorodibenzo-para-dioxin (dioxin or TCDD) recorded in humans. TCDD is the most toxic member of a class of planar, halogenated aromatic compounds. It is produced as an unwanted by-product of several industrial processes. Because TCDD is an extremely stable insoluble compound, it becomes incorporated into the food chain. Persons from industrial areas have higher TCDD levels than those from nonindustrial areas. In a recent report on rhesus monkeys exposed to five and 25 ppt of TCDD in feed, Rier et al., (1993) found the incidence and severity of endometriosis was dose-related. Although little is known about the etiology of endometriosis, it is estimated to affect over five million United States women, with a prevalence of about 10 percent among women of reproductive age. It is associated with infertility and debilitating pain. The estimated body burden for humans with background exposure to TCDD differs from the monkeys in the low dose group by less than one order of magnitude. Many residents of Seveso have been estimated to have been exposed to higher levels than the monkeys. The purpose of this proposal is to follow-up the Seveso cohort and examine their risk of endometriosis and other related reproductive endpoints. Women between zero and 25 years old at the time of the accident and who lived in Zones A and B max (the more heavily exposed areas) will be compared with those of similar age who lived in the non- exposed area, Zone non-ABR. Women will be interviewed about their reproductive history and asked to keep a menstrual cycle diary for two months. Medical records will be obtained for reported gynecologic problems. Women will receive a pelvic examination and transvaginal sonography and, if appropriate, laparoscopy. Blood samples will be drawn and analyzed for CA-125 (a marker of endometriosis), and tumor necrosis factor alpha and interleukin-6, two immunologic markers associated with both endometriosis and acute dioxin exposure. TCDD levels will be measured in sera collected in 1976 or if missing, in sera collected in 1995. Endometriosis and other related adverse reproductive outcomes are hypothesized to be dose-related to serum levels of TCDD. Women from Zone A are hypothesized to have higher rates of endometriosis than women from Zone B max and in turn than those from Zone non-ABR. The results of this study will contribute to our knowledge of etiology of endometriosis. Estrogen is considered a necessary component for the growth and maintenance of endometriosis. However, the effects of TCDD are anti-estrogenic. Confirming the association between TCDD and endometriosis in humans will shed new light on the pathophysiology of the disease. In addition, new risk factors for the disease will be identified. Further, the results of this study will have important policy implications for the regulation of exposure to TCDD and TCDD-like compounds.